Renal collecting duct plasticity revealed by intercalated cell lineage tracing

Abstract

The connecting tubule and collecting duct in the distal nephron play an essential role for acid‐base and NaCl homeostasis. Their epithelium comprises two main cell types, i.e. principal cells and intercalated cells (IC). At least two types of IC, type A‐IC and type B‐IC are distinguished. While A‐IC express the V‐type ATPase at their apical side, it localizes basolaterally in B‐IC. Thus, A‐IC can actively secrete H+, while B‐IC can mediate bicarbonate secretion via apical pendrin. Adaptation to a change in acid/base status is partly achieved by varying the numbers of A‐IC and B‐IC cells. For example, a chronic metabolic acidosis or LiCl administration promote an increase in A‐IC while the number of B‐IC is decreased. Based on these findings it is assumed that the plasticity of the distal nephron might be explained in part by a conversion of B‐IC into A‐IC or principal cell to A‐IC or vice versa.To test this hypothesis, we crossed a mouse reporter line with a Cre‐line either specific for A‐ or B‐IC. The expression of Cre‐recombinase results in the excision of a floxed STOP cassette, thus, inducing constitutive expression of TdTomato. In both mouse models, TdTomato positive cells were characterized by confocal microscopy and immunostaining with IC and principal cell markers. In untreated adult mice, the fluorescent tag was restricted to each IC population with no leakiness in PC or other renal epithelial cells. In chronic metabolic acidosis induced by NH4Cl loading or during LiCl treatment, no transition of B‐IC TdTomato+ cells to A‐IC was observed. In a similar setting of metabolic alkalosis, A‐IC tomato‐td mice did not transform in B‐IC when challenged with NaHCO3 load. In the recovery of LiCl treatment in A‐IC tagged mouse, we could detect that some principal cells acquire the TdTomato mainly in the medullary collecting duct.In conclusion, A‐ and B‐IC lineage tracing in the mouse suggest that conversion either from A‐to B‐IC or from B‐ to A‐IC does not occur in the adult mouse kidney. We observed the transition from A‐IC to principal cells in the medulla which suggests a particular plasticity between this two cell types.Support or Funding InformationNP is funded by Agence National Recherche grant ANR‐16‐CE14‐0031 and ANR‐15‐CE14‐0024. CH is funded by DFG grant HU 800/7‐2This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.